Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/04—Esters of boric acids

Definitions

• the present invention relates to a process for the preparation of 6-D- ⁇ -amino-p-hydroxyphenylacetamido penicillanic acid, which is an antibiotic generically known with the name of amoxicillin.
• amoxicillin is a product already well known, described in British Pat. No. 978,178. According to said patent, the amoxicillin is prepared by the synthesis of the 6-aminopenicillanic acid (commonly known as 6-APA) with the mixed anhydride formed by the reaction of ethyl chloroformate with O,N-dibenzyloxycarbonyl-p-hydroxy phenylglycine and subsequent removal of the protective groups by catalytic hydrogenation.
• 6-APA 6-aminopenicillanic acid
• Belgian Pat. No. 737,848 describes the synthesis of the amoxicillin from 6-APA and the mixed anhydride obtained by a Dane salt of the p-hydroxyphenylglycine and ethyl chloroformate. The intermediate products which are formed in this reaction are isolated; it is not possible to calculate the total yields of amoxicillin.
• An analogous process is described in German Patent Application DOS No. 2,520,647 where, thanks to the use of a catalyst, such as the dimethylacetamide hydrochloride, there are obtained yields up to 78%. No mention is made, however, with regard to the purity of the final product.
• British Pat. No. 1,241,844 illustrates a process in which the aminic group of the p-hydroxyphenylglycine is protected by means of the carbobenzyloxy group and the use of the p-hydroxyphenylglycine chloride hydrochloride by the reaction with 6-APA in an aqueous phase; the yields are not disclosed.
• the present invention thus relates to a process for the production of 6-D- ⁇ -amino-p-hydroxyphenyl-acetamido penicillanic acid, characterized by the fact that there are reacted a boron derivative of 6-APA of the formula ##STR1## wherein R is --H or ##STR2## n is 2 or 3, with an at least equimolar quantity of an acylating agent derived from the D(-)-p-hydroxyphenylglycine of formula (II): ##STR3## where R 1 is an alkyl radical such as methyl, ethyl and isobutyl and
• R 2 is an alkoxy radical such as methoxy and ethoxy, in a solvent selected from the group consisting of dimethylformamide alone and of dimethylsulfoxide mixed with mehylene chloride or chloroform,
• the reaction mixture is hydrolyzed with water obtaining two phases, the enaminic group is removed by lowering the pH of the reaction mixtures to 0.8-1.8 by means of the addition of an aqueous solution of an acid, from the aqueous solution containing amoxicillin hydrochloride there being isolated amoxicillin trihydrate by means of known techniques.
• the compounds of formula (I) are prepared according to the processes described in U.S. Pat. No. 4,127,571 and in Italian Patent Application No. 26,865 A/79.
• the derivatives of the p-hydrophenylglycine of formula (II) are known per se and are described in Belgian Pat. No. 737,848. Preferably they are prepared according to the method described in European Pat. No. 1,133, according to which they are prepared by the reaction of the corresponding Dane salt of the D(-)-p-hydroxyphenylglycine (selected from that formed by condensation of the p-hydroxy-phenylclycine with methyl acetoacetate or with ethyl acetoacetate) with a chloroformate selected from the group consisting of ethyl chloroformate, methyl chloroformate and isobutyl chloroformate in the presence of N-methylmorpholine or N,N-dimethylbenzylamine as catalysts.
• the removal of the protective enaminic group, at the end of the reaction, is effected by using hydrochloric acid of a concentration of about 37%.
• the phases are separated and the aqueous phase containing the amoxicillin chlorohydrate in solution is purified.
• the amoxicillin trihydrate is isolated by precipitation by the addition of an inorganic base, such as dilute ammonium hydroxide, dilute sodium hydroxide or dilute potassium hydroxide, until the pH of the mixture reaches a value of 4.7-5.2.
• an inorganic base such as dilute ammonium hydroxide, dilute sodium hydroxide or dilute potassium hydroxide
• One of the advantages obtained by the process of the present invention is constituted by the high degree of purity of the product obtained; in fact the products deriving from the hydrolysis of the boron esters are extremely soluble in water.
• Another advantage resides in the excellent yields obtained with the process of the present invention; in fact there is obtained a conversion of amoxicillin present in solution of about 97% and a yield of amoxicillin, after isolation, of about 84%, yields which are thus higher than those obtained with the known processes.
• the exotherm of the reaction is maintained within -35° C. and the mixture is allowed to react at -35° C. for 2 hours.
• the reaction mixture is cooled to -50° C.
• the mixture (b), cooled to -50° C., is added as rapidly as possible to the suspension of the mixed anhydride obtained in (a); the exotherm is maintained within -35° C. and the mixture is maintained at this temperature for 1 hour.
• One ml of reaction mixture is withdrawn and is hydrolyzed with a solution of 4 ml H 2 O and 1 ml acetone; 30-50-10 ⁇ l of the solution are placed on silica gel plate GF 254 with comparison of amoxicillin and 6-APA.
• the plate is developed with ninhydrin and there noted the appearance of a spot of amoxicillin and the absence of unreacted 6-APA.
• ninhydrin a mixture of 133 ml H 2 O and 40 ml acetone
• HCl solution 37% concentration
• the exotherm is contained within -35° C. and the reaction mixture is allowed to react at -35° C. for 2 hours. The reaction mixture is then cooled to -50° C.
• the phases are separated and the organic phase is extracted again at pH 1-1.3 with a mixture of 150 ml H 2 O and 45 ml acetone.
• the aqueous phases are combined and filtered. The exact volume is measured and on a small aliquot thereof there is carried out an HPLC titration. There are present in solution 56.7 g, equal to a theoretical yield of 97.5%, value which is also confirmed microbiologically.
• Example 2 The same process indicated in Example 2 is used, with the exception that in the phase (a) there are used 20 ml of DMSO instead of 30 ml.
• the final product is crystallized from the final aqueous solution by cooling it to 0° C. and bringing the pH to 5-5.2 with a 10% solution of KOH. Crystallization is brought about by seeding with 0.1 g of product and the solution is allowed to crystallize at 0° C. for 5 hours.
• the result solid is filtered, washed with 100 ml of water:acetone (1:1), then with 50 ml of acetone. Then the residue is dried at 40° C.
• Example 2 There is used the same process used in Example 2, except that in the phase (a) there are used 36 ml of DMSO instead of 30 ml.
• the product is isolated by crystallization obtaining 46.2 of amoxicillin, equal to a yield based on the theoretical yield of 79.5%, with a purity, measured microbiologically, of 846 mcg/mg, K.F. 14.1%.
• [ ⁇ ] D +300° on dry basis.
• Microbiological titer 851 mcg/mg
• part (c) there is crystallized amoxicillin trihydrate obtaining 44.2 g, equal to 76% of theoretical, with a microbiological purity of 851 mcg/mg and K.F. 13.8%.
• 6-APA boron ester using 30 g (0.1388 mols) of 6-APA, 30.84 g (0.304 mols) of TEA and 32.45 g of ethylene chloroboronate in methylene chloride (281 ml containing 11.52 g/100 ml).
• amoxicillin trihydrate the analytical characteristics of which are the following:
• HPLC titer 99.5% b.w. (on dry basis)
• Microbiological titer 855 mcg/mg

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=26328703

Family Applications (1)

Country Status (10)

Cited By (2)

Citations (5)

• 1979
  • 1979-11-02 IT IT27013/79A patent/IT1193836B/it active
• 1980
  • 1980-02-20 JP JP1926680A patent/JPS5671094A/ja active Pending
  • 1980-03-24 US US06/133,442 patent/US4310460A/en not_active Expired - Lifetime
  • 1980-04-07 KR KR1019800001442A patent/KR830002453B1/ko not_active Expired
  • 1980-04-24 YU YU01132/80A patent/YU113280A/xx unknown
  • 1980-05-01 GB GB8014460A patent/GB2061260B/en not_active Expired
  • 1980-05-14 DE DE19803018535 patent/DE3018535A1/de not_active Withdrawn
  • 1980-05-23 FR FR8011567A patent/FR2468609A1/fr active Granted
  • 1980-05-29 CH CH417980A patent/CH645377A5/it not_active IP Right Cessation
  • 1980-09-23 NL NL8005293A patent/NL8005293A/nl not_active Application Discontinuation

Patent Citations (6)

Also Published As

Similar Documents

Legal Events